Sustained Mood Improvement With Laughing Gas Exposure

Prior treatment

• Contraindication to receiving nitrous oxide (e.g. any condition where air is entrapped within a body and its expansion might be dangerous such as, pneumothorax, elevated intracranial pressure, air embolism, recent middle ear, vitreoretinal or bowel obstruction surgeries, etc.)
• Contraindication to receiving the placebo midazolam (e.g. shock, chronic heart failure, chronic obstructive pulmonary disease, closed-angle glaucoma, renal failure, patients with limited pulmonary reserve or those with severe decline of vital signs)
• Received electroconvulsive therapy within the past six months
• Received ketamine treatment within the past six months
• Received repetitive transcranial magnetic stimulation within the past six months

Other illness

• Diagnosis of Bipolar Disorder
• Current substance abuse or dependence and/or history of alcohol abuse or dependence within the past year
• Dementia
• Current or lifetime history of schizophrenia or schizoaffective disorder
• Known history of hypersensitivity or allergy to nitrous oxide, midazolam or any ingredients in the study formulations

Lab values

• Known chronic cobalamin or folate deficiency (e.g. signs of anemia or neurological symptoms, with plasma levels of homocysteine over 15 µmol/L and abnormal red blood cells and leukocytes on a complete blood count CBC) or current methotrexate use

Other

• Acute suicidality defined as score \> 4 on MADRS item 10
• Daily use of centrally acting medicinal products, such as opioid agonists, (e.g. naloxone and naltrexone) morphine derivatives (e.g. oxycodone, hydrocodone, oxymorphone, codeine), benzodiazepines (e.g. diazepam, clonazepam, alprazolam) and/or other central nervous system depressants such as barbiturates (e.g. phenobarbital, pentobarbital, amobarbital) and alcohol within the past week.
• Pregnancy or breastfeeding
• Unwilling to maintain current antidepressant regimen.

• 18 to 65 years of age
• Meeting Diagnostic and Statistical Manual for Mental Disorders (DSM-5) criteria for Major Depressive Disorder (MDD)
• Current major depressive episode as confirmed by the Mini International Neuropsychiatric Interview (MINI) for DSM-5
• Experiencing moderate to severe depressive episodes, as defined by the Montgomery-Åsberg Depression Rating Scale (MADRS) \> 21
• Failure of two trials of antidepressant therapy of adequate dose and duration, during the current depressive episode
• For women of childbearing potential, use of highly effective or double-barrier methods of contraception. Abstinence is acceptable if it is the preferred and usual lifestyle of the female participant
• Capacity to provide informed consent.